Human T-cell leukemia viruses (HTLV) are the etiologic agents of specific forms of leukemia/lymphomas in man. The mechanism by which these viruses transform T-cells in vitro and induce malignancies in vivo is not known. Viral replication and cellular transformation is dependent on the two virus-encoded trans-acting regulatory gene products termed Tax and Rex. Tax acts to increase the rate of transcription. The ultimate function of the Rex phosphoprotein is to increase the level of the viral structural and enzymatic proteins (Gag, Pol, and Env) expressed from the incompletely spliced viral mRNAs that contain the cis-acting Rex-response element (RxRE). The precise mechanism of Rex function is still unclear, although the current theory on how Rex achieves its effect is through binding of Rex to the RxRE and facilitating nuclear export of the incompletely spliced viral RNAs containing the RxRE to the cytoplasm. It appears that the phosphorylation state of HTLV-II Rex determines the efficiency of binding of Rex to target RNAs in vitro. Furthermore it has been proposed that the HTLV Rex protein may play a role or control the switch that determines whether virus exists in a latent or productive state. Thus, the phosphorylation state of Rex in the infected cell may provide this regulatory control. This proposal focuses on understanding the genetic and biochemical basis of HTLV-II rex gene function with particular emphasis on the importance of posttranslational modification by phosphorylation. The Specific Aims are: 1) to identify and characterize functional domains within the HTLV-II Rex protein; 2) to characterize HTLV-II Rex phosphorylation in vivo and determine its role on HTLV-II replication and cellular transformation; and 3) to characterize the kinase/phosphatase responsible for regulating Rex function. A clear picture of Rex mechanism of action will be important to understanding the pathogenesis of HTLV in man.